Suppressed but still infectious
2013; Future Medicine; Volume: 8; Issue: 11 Linguagem: Inglês
10.2217/fvl.13.89
ISSN1746-0808
AutoresSara Gianella, Richard Haubrich, Sheldon Morris,
Tópico(s)HIV, Drug Use, Sexual Risk
ResumoFuture VirologyVol. 8, No. 11 EditorialFree AccessSuppressed but still infectiousSara Gianella, Richard Haubrich & Sheldon R MorrisSara Gianella* Author for correspondenceUniversity of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA 92093-0679, USA. , Richard HaubrichUniversity of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA 92093-0679, USA & Sheldon R MorrisUniversity of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA 92093-0679, USAPublished Online:17 Oct 2013https://doi.org/10.2217/fvl.13.89AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: antiretroviral therapyCMV coinfectionseminal HIV sheddingsexual HIV transmissionsuppressed HIV RNAThe majority of HIV in the USA is transmitted through sexual intercourse. In 2011, diagnosed infections attributed to male-to-male sexual contact (65%) and those attributed to heterosexual contact (27%) accounted for approximately 92% of new HIV infections in the USA [101]. The current prevention paradigm suggests that early identification of HIV-infected individuals ('test') and early initiation of antiretroviral therapy (ART; 'treat') could lead to dramatic reductions in the incidence of HIV infection [1,2], and this 'test-and-treat' strategy for HIV prevention is supported by mathematical models and epidemiological data [2–4]. Additionally, data from a large randomized trial demonstrated a 92% reduction in HIV transmission within serodiscordant couples when the HIV-infected partner was placed on ART [3]. Nevertheless, incomplete engagement in HIV care is still common in the USA and the most recent estimate from the CDC is that only 66% of the 1.1 million Americans living with HIV are linked to care and only around one quarter have HIV RNA suppressed in plasma [102]. These incompletely engaged individuals continue to contribute to the ongoing transmission of HIV infection and pose substantial barriers to the achievement of optimal treatment outcomes. Additionally, high-risk individuals that understand the protective effect of ART on HIV transmission [5–7], and who are receiving ART (regardless of viral suppression) [8–10], have demonstrated increased risk behaviors – several studies have reported an increasing incidence of HIV among men who have sex with men (MSM), despite the widespread availability of ART [11–13]. Finally, sexual HIV transmission [14,15] and intermittent seminal HIV shedding [16] can occur even in treated individuals with undetectable HIV RNA levels in blood; it remains unclear how much of the residual risk of transmission is contributing to sustain the HIV epidemic at a population level.Seminal HIV shedding during effective ART is intermittent, and the prevalence ranges from 2% up to 48% (most studies have rates between 6 and 8%) [17–23], depending on the characteristics of the observed population. Prevalence estimates increase when repeated longitudinal sampling is employed [17]. In addition, since most studies only measured cell-free HIV RNA in seminal plasma, the detectable rate of HIV in genital secretions may actually double if cell-associated HIV DNA and RNA transcripts are also measured [18].These reported isolated seminal HIV shedding events in ART-treated individuals might be a consequence of viral compartmentalization [24] with poor drug penetration within the genital tract [16,25], or may arise from stimulation by concurrent sexually transmitted infections (STIs) and genital inflammation [17,18,26–28]. Our group has focused on identifying factors associated with HIV seminal shedding in asymptomatic MSM with and without ART [29–32]. In ART-naive MSM, we identified that seminal shedding of CMV, EBV and human herpes virus 8 were associated with increased HIV seminal shedding [29]; CMV and EBV were also associated with HIV transmission [30]. More recently, we reported that 6% of asymptomatic HIV-infected MSM on ART had detectable HIV RNA in semen, despite completely suppressed HIV RNA levels in blood, and the presence of bacterial STIs was not a major contributor to these viral shedding episodes [31]. In our study, the only independent predictor of seminal HIV RNA shedding was the concurrent detection of high-level CMV DNA in the genital tract. Another recent study on treated MSM with suppressed HIV RNA in the blood [23] observed a similar frequency of 7.6% seminal HIV shedding, which was associated with the size of the latent HIV reservoir in blood, but not with presence of STIs. The composition of the agents in the antiretroviral regimen has not generally been associated with differential shedding rates, with the exception of regimens containing raltegravir [31,33]. In our study, 4.8% of subjects on suppressive raltegravir regimens had seminal shedding compared with 9.9% on nonraltegravir-containing regimens, but this difference was not statistically significant [31].An important point, which remains to be determined, is whether the presence of detectable HIV RNA in semen at low levels while on ART (mostly found at levels <1000 copies/ml) represents a real risk of viral transmission during sexual intercourse. In addition, since the origin of transmitted virus (cell free vs cell associated) is still unresolved, the contribution of cell-associated HIV to sexual HIV transmission during suppressive ART needs to be studied further [34,35]. One study estimated heterosexual transmission using a probabilistic model for a seminal viral load of <1000 copies/ml to be 3/10,000 sexual episodes [36], and this estimate is likely to be higher during anal intercourse. Another recent study described a stepwise association between levels of genital HIV RNA and HIV transmission risk among heterosexual couples [37], with a 1 log10 increase in genital HIV RNA resulting in a 1.79–2.20-fold increased risk of HIV transmission. In this study the risk of HIV transmission was estimated at 1.4–4.4 per 100 person-years when HIV RNA in genital secretion was <3 logs. Interestingly, a total of 11 transmissions (incidence <1% per year) occurred from individuals with undetectable genital HIV RNA. However, all these subjects had detectable plasma HIV RNA levels, and the median time between collection of the genital sample from the source partner and HIV seroconversion was 4.6 months. Independently from HIV RNA levels in the genital tract, one study calculated a transmission rate of 0.37 (95% CI: 0.09–2.04) per 100 person-years for ART-treated source partners, compared with 2.24 (95% CI: 1.84–2.72) from ART-naive heterosexual partners, corresponding to a 92% reduction [3]. This is similar to a pooled estimate of transmission from heterosexuals on ART of 0.46 (95% CI: 0.19–1.09) per 100 person-years [38].Translating the individual estimates of HIV transmission risk into estimates of the overall effect of HIV spread among the growing number of ART-treated individuals is currently a challenge. We previously attempted to estimate the potential impact of HIV transmission in the USA related to MSM on ART with suppressed HIV RNA viral load [39], which gave a figure of approximately 3500 cases in 1 year. However, there are many factors that could significantly impact this estimate, and these should be accounted for. First, we used a probability of transmission of 0.00136 per act (92% reduction from the estimate in untreated men of 0.017 [40]). However, the true transmission per act during suppressive ART has not been well defined for MSM, and the 92% reduction applied to the empirically derived estimates of transmission with anal sex are higher than the mathematically modeled estimate of transmission with a seminal viral load <1000 copies/ml. Additionally, while it is relatively straight forward to estimate the number of ART-suppressed MSM living in the USA (as 25% of the 489,121 HIV-infected MSM [102,103]), there is much less certainty regarding the number of unprotected anal sex acts per year these MSM are having with serodiscordant partnerships. Changes in risk behavior (i.e., risk compensation) may also be expected to increase with further dissemination of the belief in the protective effect of ART and use of pre-exposure prophylaxis [41].Similar problems would exist when attempting to calculate the transmissions in heterosexual and injection drug users. Better accuracy and precision in the future will require a more definitive estimate of transmission probability and transmission risk behavior derived from empirical data. The point remains that with a growing number of individuals living with HIV and suppressed on ART, this group may still contribute substantially to the HIV epidemic.In conclusion, there is accumulating evidence suggesting that HIV RNA can be detected in the semen of men, despite being on suppressive ART [17–23,31]. However, the clinical significance and contribution of the detected virus to ongoing HIV transmission remains unclear. One first step to investigate the clinical significance would be to determine the threshold of detectable seminal HIV RNA associated with culture-competent virus, but these studies would be confounded by the sensitivity of viral growth assays. There are very few observational data on transmission partner pairs where the sources are receiving ART and, although difficult, this research would greatly inform the topic. For example, some important open questions to be addressed would be: is there a threshold (and what is it) or a linear relationship for seminal viral load that is associated with HIV transmission, and how is this different for heterosexual and MSM sexual transmission? What is the origin of transmitted virus (cell free vs cell associated)? Given our recent observations on asymptomatic viral coinfections [31], especially CMV, could there be important cofactors that need further consideration? Interventional research should be performed to determine whether better genital tract-penetrating ART drugs or the suppression of CMV is effective in reducing HIV shedding in semen and eventually also impacting the risk of HIV transmission. Thus, current scientific priorities should be concerned with HIV transmission from individuals on suppressive ART and how such transmission can be prevented; this agenda will require a better understanding of the attributable proportion of HIV transmission that comes from treated HIV-infected subjects, and which factors contribute to enhancing the risk of HIV RNA shedding in semen during ART.Financial & competing interests disclosureThis work was supported by the Department of Veterans Affairs, the James Pendleton Charitable Trust, amfAR grant no. 108537 with support from FAIR; NIH grant no. 7UM1AI068636-07; NIAID grant no. 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HIV surveillance report, vol. 23 (2011). www.cdc.gov/hiv/risk/gender/msm/facts/index.html (Accessed 15 August 2013)Google ScholarFiguresReferencesRelatedDetailsCited ByCondomless sex and HIV transmission among serodifferent couples: current evidence and recommendations3 May 2017 | Annals of Medicine, Vol. 49, No. 6Seminal HIV-1 RNA Detection in Heterosexual African Men Initiating Antiretroviral Therapy6 April 2016 | Journal of Infectious Diseases, Vol. 214, No. 2High incidence of diagnosis with syphilis co-infection among men who have sex with men in an HIV cohort in Ontario, Canada20 August 2015 | BMC Infectious Diseases, Vol. 15, No. 1 Vol. 8, No. 11 Follow us on social media for the latest updates Metrics History Published online 17 October 2013 Published in print November 2013 Information© Future Medicine LtdKeywordsantiretroviral therapyCMV coinfectionseminal HIV sheddingsexual HIV transmissionsuppressed HIV RNAFinancial & competing interests disclosureThis work was supported by the Department of Veterans Affairs, the James Pendleton Charitable Trust, amfAR grant no. 108537 with support from FAIR; NIH grant no. 7UM1AI068636-07; NIAID grant no. AI 064086 (K24 to R Haubrich), AI 069432 (UCSD ACTU) and AI 36214 (CFAR Clinical Investigation and Biostatistics Core); the California HIV/AIDS Research Program (CHRP: MC08-SD-700 and EI-11-SD-005); and the Interdisciplicinary Research Fellowship in NeuroAIDS R25-MH081482. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. R Haubrich has received honoraria or consultant fees from BMS, Gilead Sciences and Janssen, and research support (to UCSD) from Abbott, GlaxoSmithKline, Pfizer and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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